Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Air Force Military Medical University, Xi'an, 710032, China.
Department of Anesthesiology, Xi'an Hospital of Traditional Chinese Medicine, Xi'an, 710001, China.
Mol Neurobiol. 2021 Mar;58(3):1052-1061. doi: 10.1007/s12035-020-02171-2. Epub 2020 Oct 21.
Traumatic brain injury (TBI), which leads to high mortality and morbidity, is a prominent public health problem worldwide. Neuroinflammation involving microglia and astrocyte activation has been demonstrated to play critical role in the secondary injury induced by TBI. A1 astrocytes, which are induced by activated microglia, can directly kill neurons by secreting neurotoxic complement C3. Estrogen has been proved to possess neuroprotective effects, but the effect and underlying mechanism of estrogen on TBI-induced neuroinflammatory injury remain largely unclear. In this study, we constructed an adult male mouse model of TBI and immediately after injury treated the mice with 17β-estradiol (E2) (100 μg/kg, once every day via intraperitoneal injection) for 3 days. We found that E2 treatment significantly alleviated TBI-induced neurological deficits, neuronal injuries, and brain edema and significantly inhibited Iba1 and GFAP expression, which are markers of microglia and astrocyte activation, respectively. E2 treatment also significantly inhibited TLR4 and NF-κB protein expression, and significantly reduced the expression of the proinflammatory factors IL-1β, IL-6, and TNF-α. Moreover, E2 treatment significantly decreased the number of complement C3d/GFAP-positive cells and complement C3d protein expression. Taking these results together, we concluded that E2 treatment dramatically alleviates TBI neuroinflammatory injury by inhibiting TLR4/NF-κB pathway-mediated microglia and astrocyte activation and neuroinflammation and reducing A1-phenotype neurotoxic astrocyte activation. Our findings indicate that E2 treatment may be a potential therapy strategy for TBI-induced neuroinflammation injury.
创伤性脑损伤（TBI）导致高死亡率和发病率，是全球一个突出的公共卫生问题。已经证明，涉及小胶质细胞和星形胶质细胞激活的神经炎症在 TBI 引起的继发性损伤中发挥关键作用。由激活的小胶质细胞诱导的 A1 星形胶质细胞可以通过分泌神经毒性补体 C3 直接杀死神经元。雌激素已被证明具有神经保护作用，但雌激素对 TBI 诱导的神经炎症损伤的作用和潜在机制在很大程度上仍不清楚。在这项研究中，我们构建了成年雄性小鼠 TBI 模型，并在损伤后立即用 17β-雌二醇（E2）（100μg/kg，通过腹腔注射每天一次）治疗小鼠 3 天。我们发现，E2 治疗显著减轻了 TBI 引起的神经功能缺损、神经元损伤和脑水肿，并显著抑制了 Iba1 和 GFAP 的表达，分别为小胶质细胞和星形胶质细胞激活的标志物。E2 治疗还显著抑制了 TLR4 和 NF-κB 蛋白的表达，并显著降低了促炎因子 IL-1β、IL-6 和 TNF-α的表达。此外，E2 治疗还显著减少了补体 C3d/GFAP 阳性细胞的数量和补体 C3d 蛋白的表达。综合这些结果，我们得出结论，E2 治疗通过抑制 TLR4/NF-κB 通路介导的小胶质细胞和星形胶质细胞激活和神经炎症，减少 A1 表型神经毒性星形胶质细胞激活，显著减轻 TBI 神经炎症损伤。我们的研究结果表明，E2 治疗可能是 TBI 诱导的神经炎症损伤的一种潜在治疗策略。
